WO2003028718A1 - Nouvelles formulations de carvedilol - Google Patents

Nouvelles formulations de carvedilol Download PDF

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Publication number
WO2003028718A1
WO2003028718A1 PCT/US2002/031297 US0231297W WO03028718A1 WO 2003028718 A1 WO2003028718 A1 WO 2003028718A1 US 0231297 W US0231297 W US 0231297W WO 03028718 A1 WO03028718 A1 WO 03028718A1
Authority
WO
WIPO (PCT)
Prior art keywords
carvedilol
oral
formulations
captisol
encapsin
Prior art date
Application number
PCT/US2002/031297
Other languages
English (en)
Inventor
Choon K. Oh
Chen Wei
Ignatious Francis
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO2003028718A1 publication Critical patent/WO2003028718A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

  • This invention relates to novel formulations of carvedilol and to the use of such formulations in the treatment of hypertension, congestive heart failure and angina.
  • Carvedilol is useful in the treatment of hypertension, congestive heart failure and angina.
  • the current commercial formulation for carvedilol is immediate release, and it is administered twice daily.
  • the immediate release formulation of carvedilol is rapidly and extensively absorbed following oral administration, with the terminal elimination half-life ranging between 7-10 hours.
  • a once-daily dosing formulation for carvedilol is commercially desirable, would simplify a patient's dosing regimen and may improve compliance rates.
  • carvedilol can be formulated in novel formulations for once-daily dosing.
  • the present invention provides for the use of cyclodextrin complexes in formulations comprising carvedilol.
  • This invention also provides for the use of such formulations for the treatment of hypertension, congestive heart failure and angina.
  • the mean plasma concentrations versus time profiles of carvedilol following bolus oral and intracolonic administration of the instant formulations at 5mg/Kg in dogs are presented in Figure 1.
  • Figures 2 shows the plasma concentration of carvedilol following administration of an oral suspension at 5mg/Kg.
  • Figures 3 shows the plasma concentration of carvedilol following intracolonic administration of the captisol complex at 5mg/Kg.
  • Figures 4 shows the plasma concentration of carvedilol following intracolonic administration of the encapsin complex at 5mg/Kg.
  • compositions of carvedilol comprising carvedilol-cyclodextrin complexes.
  • the composition may then be formulated, for example, in the form of tablets or capsules. Orally administrable formulations are preferred.
  • the present invention provides for a formulation comprising carvedilol- cyclodextrin complexes.
  • carvedilol-cyclodextrin complexes refers to Carvedilol- Captisol®, sulfobutylether beta-cyclodextrin, or Carvedilol-Encapsin, hydroxypropyl beta- cyclodextrin complexes.
  • compositions containing the carvedilol-cyclodextrin complexes, thus produced, are then used in tablets for oral administration in a unit dose.
  • These oral tablets comprise conventional controlled release formulations, such as tablets, having a sustained release or an enteric coating, or otherwise modified to control the release of the active compound, for example by the inclusion of gel forming polymers or matrix forming waxes.
  • Tablets for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers and diluents (tableting or compression aids), lubricants, disintegrants, colorants, flavourings, and wetting agents.
  • excipients such as binding agents, fillers and diluents (tableting or compression aids), lubricants, disintegrants, colorants, flavourings, and wetting agents.
  • the tablets may be coated according to techniques well known in the art.
  • oral formulations may be prepared by conventional methods of blending, filling, tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, well known in the art.
  • the present invention provides for the use of a pharmaceutically acceptable organic acid in the formulations comprising carvedilol.
  • the formulation is adapted for oral administration.
  • the formulation is presented as a unit dose. Such a formulation is taken once or twice daily, preferably once daily.
  • the preferred unit dosage forms include tablets comprising beween about 25-50 mg of carvedilol. No unacceptable toxicological effects are expected when carvedilol is administered in accordance with the present invention.
  • Carvedilol-Captisol®, sulfobutylether beta-cyclodextrin, or Carvedilol-Encapsin, hydroxypropyl beta-cyclodextrin,complexes in pH 6.0 phosphate buffer results in the enhanced absorption of carvedilol in the lower GI tract.
  • Carvedilol is a novel, multiple-action cardiovascular agent that is being developed jointly by SmthKline Beecham and Boehringer Mannheim GmbH. Carvedilol is rapidly absorbed following oral administration in the rat and dog. Due to substantial first pass metabolism, the absolute bioavailability of Carvedilol in the rat and dog is low (20-25% and 10-30%, respectively).
  • Carvedilol was dosed at 5 mg/kg.
  • Intracolonic A solution of Carvedilol-Captisol® complex in water, containing 6% Captisol; Carvedilol concentration, 4.16 mg/mL.
  • Oral suspension A suspension of Carvedilol in 1 % methocel at a concentration of 4.16mg/mL.
  • Dogs Five male beagle dogs surgically prepared with duodenal and colonic vascular access ports were used. Dogs were dosed at 5 mg/kg at a dose volume of 1.2mL/kg. Vascular access ports were x-rayed for placement and patency prior to and post experiment. Dogs were fasted at least 18 hours prior to dosing. On the day of study, the dogs were placed in a sling (Alice King, Chatham Medical Arts, CA) for the first two hours, and fitted with an indwelling catheters in the forelegs to facilitate blood sampling. After two hours post dosing, the dogs were put back in their cages with free access to water and blood samples taken as appropriate. Food was returned to each dog 8 hours post dosing.
  • a sling Alice King, Chatham Medical Arts, CA
  • a 9 mm stomach tubing (20-25 cm) was employed and the dosing solution was followed with 100ml of MilliQ water.
  • Dog plasma samples were assayed by levels of carvedilol. Quantitation was performed by LC MS/MS employing positive-ion electrospray ionisation. A 200microliter aliquot of the sample was used. The LLQ (lower limit of quantification) was 0.5ng/mL and HLQ (high limit of quantification) was 150ng/mL.
  • Captisol and Encapsin complexes of Carvedilol administered intracolonically This is inspite of the fact that Captisol complex is given as a clear liquid, due to its higher aqueous solubility, compared to Encapsin complex being a suspension. It might be speculated that there is not enough fluid in the dog colon to bring about the complete dissociation of the Carvedilol- Captisol complex. The scenario might be different in the human lower GI tract.
  • Encapsin-IC/ Oral 20 64 23 62 31 40 ⁇ 10

Abstract

La présente invention porte sur de nouvelles formulations renfermant du carvedilol ainsi que sur des méthodes d'utilisation de ces formulations dans le traitement de l'hypertension, de l'insuffisance cardiaque congestive et de l'angine de poitrine.
PCT/US2002/031297 2001-10-01 2002-10-01 Nouvelles formulations de carvedilol WO2003028718A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32636801P 2001-10-01 2001-10-01
US60/326,368 2001-10-01

Publications (1)

Publication Number Publication Date
WO2003028718A1 true WO2003028718A1 (fr) 2003-04-10

Family

ID=23271908

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/031297 WO2003028718A1 (fr) 2001-10-01 2002-10-01 Nouvelles formulations de carvedilol

Country Status (1)

Country Link
WO (1) WO2003028718A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7268156B2 (en) 2002-06-27 2007-09-11 Sb Pharmco Puerto Rico Inc. Carvedilol phosphate salts and/or solvates thereof, corresponding compositions and/or methods of treatment
WO2007124869A2 (fr) * 2006-05-02 2007-11-08 Bayer Animal Health Gmbh Formulation de médicament liquide
WO2009079679A3 (fr) * 2007-12-21 2009-11-26 Aop Orphan Pharmaceuticals Ag Composition pharmaceutique
US7649010B2 (en) 2002-06-27 2010-01-19 SmithKline Beechman Cork Limited Carvedilol hydrobromide
US7750036B2 (en) 2003-11-25 2010-07-06 Sb Pharmco Puerto Rico Inc. Carvedilol salts, corresponding compositions, methods of delivery and/or treatment
US10772869B1 (en) 2019-07-24 2020-09-15 ECI Pharmaceuticals, LLC Pharmaceutical compositions including carvedilol and methods of using the same

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4503067A (en) * 1978-04-13 1985-03-05 Boehringer Mannheim Gmbh Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US5874418A (en) * 1997-05-05 1999-02-23 Cydex, Inc. Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use
US5902821A (en) * 1995-02-08 1999-05-11 Boehringer Mannheim Pharmaceuticals Corporation Smith Kline Corporation Limited Partnership No. 1 Use of carbazole compounds for the treatment of congestive heart failure
US5904929A (en) * 1996-12-25 1999-05-18 Janssen Pharmaceutica, N.V. Acylated cyclodextrin-containing pharmaceutical composition

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4503067A (en) * 1978-04-13 1985-03-05 Boehringer Mannheim Gmbh Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US5902821A (en) * 1995-02-08 1999-05-11 Boehringer Mannheim Pharmaceuticals Corporation Smith Kline Corporation Limited Partnership No. 1 Use of carbazole compounds for the treatment of congestive heart failure
US5904929A (en) * 1996-12-25 1999-05-18 Janssen Pharmaceutica, N.V. Acylated cyclodextrin-containing pharmaceutical composition
US5874418A (en) * 1997-05-05 1999-02-23 Cydex, Inc. Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7268156B2 (en) 2002-06-27 2007-09-11 Sb Pharmco Puerto Rico Inc. Carvedilol phosphate salts and/or solvates thereof, corresponding compositions and/or methods of treatment
US7902378B2 (en) 2002-06-27 2011-03-08 Smithkline Beecham (Cork) Limited Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7893100B2 (en) 2002-06-27 2011-02-22 Sb Pharmco Puerto Rico Inc. Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7759384B2 (en) 2002-06-27 2010-07-20 Smithkline Beecham (Cork) Limited Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7626041B2 (en) 2002-06-27 2009-12-01 Smithkline Beecham (Cork) Ltd Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7649010B2 (en) 2002-06-27 2010-01-19 SmithKline Beechman Cork Limited Carvedilol hydrobromide
US7750036B2 (en) 2003-11-25 2010-07-06 Sb Pharmco Puerto Rico Inc. Carvedilol salts, corresponding compositions, methods of delivery and/or treatment
WO2007124869A3 (fr) * 2006-05-02 2008-04-17 Bayer Healthcare Ag Formulation de médicament liquide
WO2007124869A2 (fr) * 2006-05-02 2007-11-08 Bayer Animal Health Gmbh Formulation de médicament liquide
WO2009079679A3 (fr) * 2007-12-21 2009-11-26 Aop Orphan Pharmaceuticals Ag Composition pharmaceutique
US10660964B2 (en) 2007-12-21 2020-05-26 Aop Orphan Pharmaceuticals Ag Pharmaceutical composition for the parenteral administration of ultrashort-effective beta-adrenoreceptor antagonists
US11517624B2 (en) 2007-12-21 2022-12-06 Aop Orphan Pharmaceuticals Gmbh Pharmaceutical composition for the parenteral administration of ultrashort-effective β-adrenoreceptor antagonists
US10772869B1 (en) 2019-07-24 2020-09-15 ECI Pharmaceuticals, LLC Pharmaceutical compositions including carvedilol and methods of using the same
US10959985B1 (en) 2019-07-24 2021-03-30 ECI Pharmaceuticals, LLC Pharmaceutical compositions including carvedilol and methods of using the same

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